Indan derivatives used for treating thromboses or asthma

ABSTRACT

Method for the treatment or prophylaxis of thromboses or asthma in warm-blooded animal which comprises administering an effective amount of a compound having the formula: ##STR1## wherein R 1  is phenyl group or phenyl group substituted by a member selected from the group consisting of C 1  -C 5  alkyl, C 1  -C 5  alkoxy, halogen atom, trifluoromethyl, and nitro, or naphthyl group, and R 2  is hydroxymethyl or a group of the formula: ##STR2## wherein R 3  is hydrogen atom or C 1  -C 5  alkyl and R 4  is C 3  -C 6  cycloalkyl, C 2  -C 6  alkoxycarbonyl-phenyl, carboxy-phenyl, C 1  -C 5  alkyl, or C 1  -C 5  alkyl having a substituent selected from C 1  -C 5  alkoxycarbonyl, carboxy, C 2  -C 6  alkoxycarbonyl-phenyl, carboxy-phenyl, C 2  -C 6  alkoxycarbonyl-(C 3  -C 6 ) cycloalkyl and carboxy-(C 3  -C 6 ) cycloalkyl, or a pharmaceutically acceptable salt thereof to said warm blooded animal.

This invention is a continuation-in-part of U.S. Ser. No. 07/688,246filed on Apr. 22, 1991, which is in turn a divisional application ofU.S. Ser. No. 07/271,324 filed on Nov. 15, 1988, now U.S. Pat. No.5,030,652.

FIELD OF THE INVENTION

This invention relates to novel indan derivatives and processes for thepreparation thereof.

PRIOR ART

Thromboxan A₂ (hereinafter, referred to as "TxA₂ ") is a metabolite ofarachidonic acid which exists widely in various organs of animals (e.g.liver, kidney, lung, brain, etc.) Said TxA₂ is known to show plateletaggregation activity and induces a variety of thrombosis such asperipheral vascular thrombosis, pulmonary embolism, coronary arterythrombosis, myocardial infarction, transient ischemia, and the like.Therefore, 4-(2-benzenesulfonylaminoethyl)phenoxyacetic acid which hasTxA₂ -antagonistic activity has been suggested to be useful fortherapeutic treatment of these diseases (cf. Thrombosis Research, 35,379-395, 1984).

SUMMARY DESCRIPTION OF THE INVENTION

As a result of various investigations, there has been found novel indanderivatives which show stronger TxA₂ antagonistic activity as comparedwith the above known compound.

Thus, the objects of the invention are to provide novel indanderivatives and a pharmaceutical composition containing the same.Another object of the invention is to provide processes for preparingsaid compounds. A further object of the invention is to provide novelintermediates which are useful in the synthesis of the indan derivativesof the invention. These and other objects and advantages of theinvention will be apparent to those skilled in the art from thefollowing description.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to indan derivative of the formula: ##STR3##wherein R¹ is a substituted or unsubstituted phenyl group, naphthylgroup or a sulfur-containing heterocyclic group, and R² is hydroxymethylgroup or a group of the formula: ##STR4## wherein R³ is hydrogen atom ora lower alkyl group and R⁴ is a cycloalkyl group, a loweralkoxycarbonyl-phenyl group, carboxy-phenyl group, a nitrogen-containingheterocyclic group, a lower alkyl group, or a lower alkyl group having asubstituent selected from a lower alkoxycarbonyl group, carboxy group, alower alkoxycarbonyl-phenyl group, carboxy-phenyl group, a loweralkoxycarbonyl-cycloalkyl group and a carboxy-cycloalkyl group, or apharmaceutically acceptable salt thereof.

Said indan derivative and a salt thereof show potent TxA₂ antagonisticand/or platelet aggregation-inhibiting activities and are useful for thetherapeutic treatment, amelioration and/or prophylaxis of a variety ofthrombosis or emolism, coronary and cerebral vascular smooth musclevellication, asthma, and the like.

Examples of the novel indan derivatives of the invention are those ofthe formula (I) wherein R¹ is phenyl group; a phenyl group substitutedby a member selected from the group consisting of a lower alkyl group(e.g. methyl, ethyl, propyl, butyl, or pentyl), a lower alkoxy group(e.g. methoxy, ethoxy, propoxy, butoxy, or pentoxy), a halogen atom(e.g. fluorine, chlorine or bromine), trifluoromethyl, or nitro;naphthyl group; or a sulfur-containing heterocyclic group (e.g. thienylgroup, etc.); R² is a hydroxymethyl group, or a group of the formula:##STR5## where R³ is hydrogen atom or a lower alkyl group (e.g. methyl,ethyl, propyl, butyl, or pentyl), and R⁴ is a cycloalkyl group (e.g.cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), a loweralkoxycarbonyl-phenyl group (e.g. methoxycarbonylphenyl,ethoxycarbonylphenyl, etc.), a carboxy-phenyl group, anitrogen-containing heterocyclic group (e.g. tetrazolyl, etc.), a loweralkyl group (e.g. methyl, ethyl, propyl, butyl, or pentyl), or a loweralkyl group (e.g. methyl, ethyl, propyl, butyl or phentyl) having asubstituent selected from a lower alkoxycarbonyl group (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxy group,a lower alkoxycarbonyl-phenyl group (e.g. methoxycarbonylphenyl,ethoxycarbonylphenyl, etc.), carboxyphenyl group, a loweralkoxycarbonyl-cycloalkyl group (e.g. methoxycarbonylcyclohexyl, etc.),and a carboxycycloalkyl group (e.g. carboxycyclohexyl group, etc.).

Among them, preferred examples of the compounds of the invention arethose of the formula (I) wherein R¹ is phenyl, a (C₁ -C₅)alkyl-phenyl, a(C₁ -C₅)alkoxy-phenyl, a halogenophenyl, trifluoromethylphenyl,nitrophenyl, naphthyl, or thienyl, R² is hydroxymethyl, or a group ofthe formula: ##STR6## wherein R³ is hydrogen atom or a (C₁ -C₅)-alkyl,and R⁴ is a (C₃ -C₆)cycloalkyl, a (C₂ -C₆)alkoxy-carbonyl-phenyl,carboxyphenyl, tetrazolyl, a (C₁ -C₅)alkyl, or a (C₁ -C₅)alkyl having asubstituent selected from a (C₂ -C₆)alkoxycarbonyl, carboxy, a (C₂-C₆)alkoxycarbonyl-phenyl, carboxyphenyl, a (C₂ -C₆)alkoxycarbonyl-(C₃-C₆)cycloalkyl and a carboxy-(C₃ -C₆)cycloalkyl.

Another preferred examples of the compounds of the invention are thoseof the formula (I) wherein R¹ is a (C₁ -C₅)alkyl-phenyl, a (C₁-C₅)alkoxy-phenyl, a halogenophenyl, trifluoromethylphenyl, nitrophenyl,or naphthyl, R³ is hydroxymethyl or a group of the formula: ##STR7##wherein R³ is hydrogen atom or a (C₁ -C₅)alkyl, and R⁴ is carboxyphenyl,tetrazolyl, a (C₁ -C₅)alkyl, a (C₂ -C₆)alkoxycarbonyl(C₁ -C₅)alkyl or acarboxy-(C₁ -C₅)alkyl.

More preferred examples of the compounds of the invention are those ofthe formula (I) wherein R¹ is a halogenophenyl, and R² is a group of theformula: ##STR8## wherein R³ is hydrogen atom and R⁴ is carboxyphenyl, a(C₂ -C₄)alkoxycarbonyl-(C₁ -C₅)alkyl or a carboxy-(C₁ -C₅)alkyl.

Further preferred examples of the compounds of the invention are thoseof the formula (I) wherein R¹ is chlorophenyl, and R² is a group of theformula: ##STR9## wherein R³ is hydrogen atom, and R⁴ is carboxyphenylor a carboxy(C₁ -C₃)alkyl.

Most preferred examples of the compounds of the invention are those ofthe formula (I) wherein R¹ is chlorophenyl, and R² is a group of theformula: ##STR10## wherein R³ is hydrogen atom, and R⁴ is carboxyethylor carboxypropyl.

The compounds (I) of the invention may exist in the form of two or fouroptically active isomers due to one or two asymmetric carbon atom(s),and this invention includes these optically active isomers and a mixturethereof.

According to this invention, the compounds (I) or salts thereof can beprepared by various processes as mentioned below.

Process A

The compounds (I) can be prepared by condensing a 2-aminoindanderivative of the formula: ##STR11## wherein R² is as defined above, ora salt thereof with a sulfonic acid compound of the formula:

    R.sup.1 SO.sub.3 H                                         (III)

wherein R¹ is as defined above, or a reactive derivative thereof.

The condensation reaction of the aminoindan (II) or a salt thereof (e.g.a mineral acid salt or an organic acid salt) and the sulfonic acidcompound (III) or a reactive derivative thereof can be carried out inthe presence or absence of an acid acceptor. The reactive derivative ofthe compound (III) includes any conventional reactive derivative, forexample, the corresponding sulfonyl halide. The acid acceptor includesany conventional agents, for example, alkali metal carbonates, alkalimetal hydrogen carbonates, trialkylamines, pyridine, and the like. Thereaction is preferably carried out in a suitable solvent (e.g. water,ethyl acetate) at a temperature of 0° to 200° C.

Process B

The compounds of the formula (I) wherein R² is hydroxymethyl, i.e. thecompounds of the formula (I-a): ##STR12## wherein R¹ is as definedabove, can be prepared by reducing a compound of the formula: ##STR13##wherein R¹ is as defined above.

The reduction of the compound (IV) can be carried out by treating itwith a reducing agent. The reducing agent includes, for example, borane1,4-oxathiane complex. This reduction is preferably carried out in anappropriate solvent (e.g. tetrahydrofuran) at a temperature of 0° to 50°C.

Process C

The compounds of the formula (I) wherein R² is a group of the formula:##STR14## i.e. the compounds of the formula (I-b): ##STR15## wherein R¹,R³ and R⁴ are as defined above can be prepared by condensing a compoundof the formula (IV) or a reactive derivative at the carboxyl groupthereof with an amine compound of the formula:

    R.sup.3 --NH--R.sup.4                                      (V)

wherein R³ and R⁴ are as defined above or a salt thereof.

The condensation reaction of the compound (IV) or a reactive derivativeat carboxyl group thereof with the amine compound (V) can be carried outby any conventional method. For example, the condensation reaction ofthe free carboxylic acid (IV) and the compound (V) can be carried out inthe presence of a dehydrating agent. The dehydrating agent includes, forexample, carbonyldiimidazole, dicyclohexylcarbodiimide, and the like.Besides, the condensation reaction of the reactive derivative at thecarboxyl group of the compound (IV) with the compound (V) can be carriedout in the presence or absence of an acid acceptor. A variety of thereactive derivative at the carboxyl group of the compound (IV),including, for example, acid halides, activated esters may be used forthe condensation reaction. The acid acceptor includes alkali metalcarbonates, alkali metal hydrogen carbonates, trialkylamines, pyridine,and the like. These reactions are preferably carried out in anappropriate solvent (e.g. tetrahydrofuran, methylene chloride) at atemperature of 0° to 50° C.

Process D

The compounds of the formula (I) wherein R² is a group of the formula:##STR16## i.e. the compounds of the formula (I-c): ##STR17## wherein R⁵is carboxy-phenyl group or a lower alkyl group having a substituentselected from carboxy group, carboxyphenyl group and acarboxy-cycloalkyl group, and R¹ and R³ are as defined above, can beprepared by hydrolyzing a compound of the formula (I-d): ##STR18##wherein R⁶ is a lower alkoxycarboxy-phenyl group or a lower alkyl grouphaving a substituent selected from a lower alkoxycarbonyl group, a loweralkoxycarboxy-phenyl group and a lower alkoxycarbonyl-cycloalkyl group,and R¹ and R³ are as defined above.

The hydrolysis of the compound (I-d) can be carried out by aconventional method, for example, by treating the compound with analkali agent or an acid. Examples of the alkali agent are alkali metalhydroxides, and examples of the acid are mineral acids. The hydrolysisis preferably carried out in an appropriate solvent (e.g. water, a loweralcohol) at a temperature of 0° to 30° C.

All of the above reactions in Processes A to D proceed withoutracemization, and hence, when an optically active compounds are used asthe starting materials, the desired compounds (I) can be obtained in theoptically active form.

The starting compound (II) wherein R² is hydroxymethyl group can beprepared, for example, by the steps of condensing a 2-(N-protectedamino)indan with a lower alkyl ester of the compound of the formula:

    Z--CH(X)--COOH                                             (VI)

wherein X is a halogen atom and Z is a lower alkylmercapto group or asubstituted or unsubstituted phenylmercapto group, removing thesubstituted mercapto group from the product to give a lower alkyl[2-(N-protected amino)indan-5-yl]acetate, hydrolyzing the product byconventional method, reducing the thus-obtained [2-[N-protectedamino)indan-5-yl]acetic acid, and then removing the protecting groupfrom the product by conventional method.

On the other hand, the compound (II) wherein R² is a group of theformula: ##STR19## can be prepared, for example, by the steps of

(a) condensing a 2-(N-protected amino)indan with a compound of theformula: ##STR20## wherein R³, R⁴, X and Z are as defined above,removing the substituted mercapto group from the product to give acompound of the formula: ##STR21## wherein R⁷ is a protecting group andR³ and R⁴ are as defined above, or

(b) condensing a [2-(N-protected amino)indan-5-yl]acetic acid or areactive derivative thereof with the amine compound (V) to give thecompound (VIII), and

(c) removing the protecting group from the compound (VIII) byconventional method.

Further, the starting compound (IV) can be prepared, for example, by thesteps of removing the protecting group from a lower alkyl[2-(N-protected amino)indan-5-yl]acetate, condensing the product withthe sulfonic acid compound (III) or a reactive derivative thereof, andhydrolyzing the product by conventional method.

The condensation reaction of the 2-(N-protected amino)indan with thecompound (VI) or (VII) can be carried out in an appropriate solvent inthe presence of Lewis acid (e.g., stannic chloride, aluminum chloride)under cooling. The amino-protecting group includes any conventionalprotecting groups, for example, acyl groups such as benzyloxycarbonyl,formyl, a lower alkoxycarbonyl group. The removal of the substitutedmercapto group from the resulting condensation product can be carriedout by heating it under an acidic condition in the presence of a heavymetal (e.g. zinc, iron), or by heating in hydrogen atmosphere in thepresence of a catalyst such as Raney nickel in an alcohol solvent. Onthe other hand, the reduction of the [2-(N-protectedamino]indan-5-yl]acetic acid, the condensation reaction of the[2-(N-protected amino)indan-5-yl]acetic acid or a reactive derivativethereof with the amine compound (V) and the condensation reaction of thelower alkyl (2-aminoindan-5-yl)acetate with the sulfonic acid compound(III) or a reactive derivative thereof can be carried out in the samemanner as described in either one of Processes (A) to (D).

The compounds (I) of this invention can be used for pharmaceutical useeither in the form of a free base or a salt. For the pharmaceutical use,the salt of the compounds is preferably pharmaceutically acceptablesalts, for example, inorganic or organic acid salts such as alkali metalsalts (e.g. sodium salt, potassium salt), alkaline earth metal salts(e.g. calcium salt, magnesium salt), heavy metal salts (e.g. zinc salt),ammonium salt, organic amine salts (e.g. triethylamine salt, pyridinesalt, ethanolamine salt, a basic amino acid salt), and the like. Thesesalts may readily be prepared by treating the compounds (I) with thecorresponding inorganic or organic base in an appropriate solvent.

The compounds (I) or a salt thereof may be administered either orally orparenterally and may also be used in the form of a pharmaceuticalpreparation containing the same compound in admixture withpharmaceutical excipients suitable for oral or parenteraladministration. The pharmaceutical preparations may be in solid formsuch as tablets, capsules and powders, or in liquid form such assolutions, suspensions or emulsions. Moreover, when administeredparenterally, it may be used in the form of injections.

As mentioned hereinbefore, the compounds (I) or a salt thereof of thisinvention show potent TxA₂ antagonistic activity and hence are useful asplatelet aggregation-inhibiting agent and are also useful for thetreatment, amelioration and/or prophylaxis of a variety of thrombosis orembolism, such as cerebral thrombosis, coronary artery thrombosis,pulmonary thrombosis, pulmonary embolism, peripheral vascular embolism,thromboangiitis, and the like. Moreover, the compounds (I) or a saltthereof are useful for the treatment, amelioration and/or prophylaxis ofmyocardial ischemia, unstable angina pectoris, coronary vellication,cerebral blood vessl vellication after subarachnoid hemorrhage, cerebralhemorrhage, asthma, and the like. Besides, although some known TxA₂antagonists show excellent TxA₂ antagonistic activity but at the sametime show transient TxA₂ -like activity and hence has side effects suchas platelet aggregation-inducing activity, broncho-constrictionactivity, blood vessel constriction activity, the compounds (I) of thisinvention do not show such TxA₂ -like activity when administered eitherorally or parenterally.

Throughout the specification and claims, the term "lower alkyl", "loweralkoxy" and "cycloalkyl" should be interpreted as referring to alkylhaving 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, andcycloalkyl having 3 to 6 carbon atoms, respectively.

The pharmacological activity and processes for the preparation of thecompounds of this invention are illustrated by the followingExperiments, Examples and Reference Examples.

EXPERIMENT

Inhibiting effect on arachidonic acid-induced pulmonary embolism (invivo):

A test compound in an aqueous carboxymethylcellulose solution (20 ml/kg)was orally administered to ddy-male mice fasted overnight. Three hourslater, arachidonic acid (125 mg/kg) was injected to the tail vein ofmice to induce pulmonary embolism, and the recovery time (minute) oflocomotive activity of the mice was compared with that of a controlgroup of mice to which a 0.25% aqueous CMC solution was administeredinstead of the test compound solution. The inhibiting effect of eachtest compound on arachidonic acid-induced pulmonary embolism wasestimated in terms of the dose required to shorten the recovery time byat least 15% as compared with the control group. The results are shownin Table 1.

                  TABLE 1                                                         ______________________________________                                        Test compound                                                                            Inhibiting effect on arachidonic acid-                             No.*       pulmonary embolism (in vivo) (mg/kg)                               ______________________________________                                        Compounds of this invention                                                   1          0.03                                                               2          0.03                                                               Control    30                                                                 ______________________________________                                        *Chemical name of test compounds are as follows.                              Compd. No.                                                                             Chemical name                                                        1:       Sodium 3-[[2-[(4-chlorophenyl)sulfonylamino]-                                 indan-5-yl]acetylamino]-n-propionate                                 2:       Sodium 4-[[2-[(4-chlorophenyl)sulfonylamino]-                                 indan-5-yl]acetylamino]-n-butyrate                                   Control: 4-(2-Benzensulfonylaminoethyl)phenoxyacetic                                   acid (a compound disclosed in Thrombosis                                      Research, 35, 379-395, 1984)                                     

EXAMPLE 1

(1) (2-Formylaminoindan-5-yl)acetic acid (219 mg) andcarbonyldiimidazole (162 mg) are mixed with stirring in a mixed solventof tetrahydrofuran-methylene chloride under ice cooling and the mixtureis stirred at room temperature for one hour, and to the reaction mixtureare added methyl β-aminopropionate hydrochloride (140 mg) andtriethylamine (100 mg), and the mixture is stirred at room temperaturefor 2 hours. After the reaction, methanol is added to the mixture, andthe solvent is distilled off under reduced pressure. The residue isseparated and purified by silica gel column chromatography (solvent,chloroform - methanol=19:1) and then recrystallized from ethyl acetate -n-hexane to give methyl3-[(2-formylaminoindan-5-yl)acetylamino]-n-propionate (238 mg) m.p.108°-110° C.

(2) The above product (200 mg) is dissolved in 5% methanol-hydrochloricacid, and the mixture is stirred at room temperature for 24 hours. Afterthe reaction, the solvent is distilled off, and the residue isrecrystallized from methanol - diethyl ether to give methyl3-[(2-aminoindan-5-yl)acetylamino]-n-propionate hydrochloride (152 mg)as colorless needles. m.p. 195°-197° C.

(3) A mixture of the free base of the above product (138 mg),4-chlorophenylsulfonyl chloride (106 mg), potassium carbonate (138 mg)and ethyl acetate (10 ml) - water (5 ml) is stirred at room temperaturefor one hour. After the reaction, the organic layer is taken, washed,dried, and then distilled to remove the solvent. The residue isrecrystallized from ethyl acetate - n-hexane to give methyl3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionate(200 mg).

m.p. 147°-150° C.,

MS (m/e): 450 (M⁺),

IR ν_(max) ^(nujol) cm⁻¹ : 3380, 1715, 1650

EXAMPLE 2

(1) In the same manner as described in Example 1-(1),(2-formylaminoindan-5-yl)acetic acid (2.20 g) and methyl γ-aminobutyrateare reacted to give methyl4-[(2-formylaminoindan-5-yl)acetylamino]-n-butyrate (2.57 g).

m.p. 89°-93° C.

(2) The above product (187 mg) is treated in the same manner asdescribed in Example 1-(2) to give methyl4-[(2-aminoindan-5-yl)acetylamino]-n-butyrate hydrochloride (165 mg).

m.p. 198°-200° C.

(3) The above product (425 mg) and 4-chlorophenylsulfonyl chloride (276mg) are treated in the same manner as described in Example 1-(3) to givemethyl4-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-butyrate(571 mg).

m.p. 128°-129° C. (recrystallized from ethyl acetate-n-hexane)

MS (m/e): 464 (M⁺)

IR ν_(max) ^(nujol) cm⁻¹ : 3360, 3280, 1735, 1720, 1650

EXAMPLE 3

(1) In the same manner as described in Example 1-(1),2-(benzyloxycarbonylamino)indan-5-acetic acid and methyl γ-aminobutyrateare reacted to give methyl4-[(2-benzyloxycarbonylaminoindan-5-yl)acetylamino]-n-butyrate.

m.p 128°-130° C.

(2) The above product (917 mg) is dissolved in a mixture oftetrahydrofuran--water, and is subjected to catalytic reduction in thepresence of 10% palladium-carbon under atmospheric pressure at roomtemperature. Two hours later, the catalyst (200 mg) is further added,and the mixture is further reacted for one hour. After the catalyst isfiltered off, the filtrate is distilled. The residue is treated withmethanol-hydrogen chloride to give hydrochloride of the product, whichis recrystallized from methanol - isopropyl alcohol - isopropyl ether togive methyl 4-[(2-aminoindan-5-yl)acetylamino]-n-butyrate hydrochloride(518 mg) as colorless needles. m.p. 200°-201° C.

(3) The above product is treated in the same manner as described inExample 1-(3) to give methyl4-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-butyrate.

m.p. 128°-129° C. (recrystallized from ethyl acetate-n-hexane)

MS (m/e): 464 (M⁺)

EXAMPLE 4

(1) To a solution of 2-formylaminoindan (3.22 g) and methyl3-[chloro(phenylthio)acetylamino]-n-propionate (6.04 g) in methylenechloride is added dropwise a solution of stannic chloride (15.6 g) inmethylene chloride at -3° to -1° C., and the mixture is stirred at roomtemperature for 5 hours. The reaction mixture is poured into water, andthereto is added chloroform. The organic layer is separated, washed anddried and then concentrated under reduced pressure. The residue isseparated and purified by silica gel column chromatography (solvent,ethyl acetate) to give methyl3-[(2-formylaminoindan-5-yl)(phenylthio)acetylamino]-n-propionate (5.21g) as colorless oil.

IR ν_(max) ^(nujol) cm⁻¹ : 3290, 1735, 1650

(2) To a solution of the above product (3.1 g) in acetic acid is addedzinc dust (9.8 g), and the mixture is refluxed with stirring for 2hours. After cooling, zinc dust is removed by filtration, and thesolvent is distilled off, and the residue is dissolved in chloroform.The solution is washed with saturated aqueous saline solution, dried,and then the solvent is distilled off. The residue is separated andpurified by silica gel column chromatography (solvent,chloroform:methanol=19:1) and recrystallized from ethyl acetate -n-hexane to give methyl3-[(2-formylaminoindan-5-yl)acetylamino]-n-propionate (1.54 g) ascolorless crystals. m.p. 108°-110° C.

(3) To a solution of the above product (2 g) in methanol is added 5%hydrochloric acid--methanol, and the mixture is reacted at roomtemperature for 24 hours. The solvent is distilled off from the reactionmixture, and the residue is crystallized from isopropyl ether--diethylether to give methyl 3-[(2-aminoindan-5-yl)acetylamino]-n-propionatehydrochloride (1.52 g) as colorless needles.

m.p. 195°-197° C.

(4) The free base of the above product (2.76 g) is added to a mixture ofethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonatesolution (100 ml) with stirring, and thereto is further added4-chlorophenylsulfonyl chloride (2.11 g), and the mixture is stirred atroom temperature for 1.5 hour. The ethyl acetate layer is separated,dried, and then the solvent is distilled off under reduced pressure. Theresidue is crystallized from ethyl acetate - n-hexane to give methyl3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionate(4.06 g) as colorless needles. m.p. 147°-150° C.

EXAMPLE 5

To a solution of methyl 4-[(phenylthio)acetylamino]-n-butyrate (6.42 g)in methylene chloride (20 ml) is added dropwise a solution of sulfurylchloride (3.42 g) in methylene chloride (10 ml). Said dropwise additionis carried out under argon atmosphere with ice-cooling for 10 minutes.The mixture is stirred at the same temperature for one hour. The solventis distilled off, and the residue is dissolved in methylene chloride (40ml). 2-Formylaminoindan (3.22 g) is added to the solution and a solutionof stannic chloride (11.5 g) and nitromethane (2.75 g) in methylenechloride (20 ml) are added thereto below 10° C. for 15 minutes, and themixture is stirred at room temperature for 8 hours. After the reaction,water (30 ml) is added to the mixture, and the mixture is stirred for 20minutes. Chloroform (30 ml) is added to the mixture, and the mixture iswashed with 10% hyrochloric acid and dried. The solvent is distilledoff, and the residue is dissolved in acetic acid (50 ml). Zinc dust (1.3g) is added to the solution under reflux, and the mixture is refluxedfor 15 minutes. After cooling, zinc dust is removed by filtration, andthe solvent is distilled off, and the residue is dissolved in chloroform(100 ml). The solution is washed with an aqueous saline solutioncontaining potassium carbonate (1 g), dried, and then the solvent isdistilled off. Ethyl acetate (30 ml) is added to the residue, and themixture is extracted with water. The solvent is distilled off, and 12.5%hydrogen chloride-methanol solution (80 ml) is added to the residue, andthe mixture is stirred at room temperature for 17.5 hours. The solventis distilled off, and the residue is dissolved in a mixture of water (30ml) and toluene (25 ml). Potassium carbonate (5.03 g) and4-chlorophenylsulfonyl chloride (3.39 g) are added to the solution, andthe mixture is stirred. After the reaction, the mixture is extractedwith a mixture of ethyl acetate and tetrahydrofuran, and the extract iswashed with an aqueous saline solution, and dried. The solvent isdistilled off, and the residue is recrystallized from a mixture ofmethanol and ethere to give methyl4-[[2-[(4-chlorophenyl)sulfonylamino]-indan-5-yl]acetylamino]-n-butyrate(4.53 g) as colorless powder.

m.p. 126.5°-127.5° C.

EXAMPLES 6 TO 23

In the same manner as described in any one of Examples 1 to 5, thecorresponding starting compounds are treated to give the compounds ofthe following Table 2.

                                      TABLE 2                                     __________________________________________________________________________     ##STR22##                                       (A)                          Ex.                                                                              Compound A                                                                 No.                                                                              R.sup.1    R.sup.3                                                                          R.sup.4        Physical properties, etc.                     __________________________________________________________________________     6                                                                                ##STR23## H  CH.sub.2 CO.sub.2 CH.sub.3                                                                   MS (m/e): 436 (M.sup.+) IR                                                    ν.sub.max.sup.nujol cm.sup.-1 : 1745,                                      1670                                           7 "          H                                                                                 ##STR24##     m.p. 199.5-200.5° C. (re- cryst.                                       from THF-hexane) MS (m/e): 512 (M.sup.+)                                      IR ν.sub.max.sup.nujol cm.sup.-1 :                                         3260, 1710, 1670                               8 "          H                                                                                 ##STR25##     m.p. 203-204° C. (recryst. from                                        THF-isopropyl ether) MS (m/e): 446                                            (M.sup.+) IR ν.sub.max.sup.nujol                                           cm.sup. -1 : 3350, 3130, 1670                  9 "          CH.sub.3                                                                         CH.sub.3       m.p. 146.5-148° C. (recryst.                                           from isopropanol-isopropyl                                                    ether)                                                                        MS (m/e): 392 (M.sup.+)                                                       IR ν.sub.max.sup.nujol cm.sup.-1 :                                         3180, 1630                                    10                                                                                ##STR26## H  C.sub.2 H.sub.5                                                                              m.p. 148-150° C. (recryst. from                                        ethanol-n-hexane) MS (m/e): 392 (M.sup.+)                                     R ν.sub.max.sup.nujol cm.sup.-1 :                                          3310, 3270, 1640                              11 "          H  CH(CH.sub.3).sub.2                                                                           m.p. 165-166° C. (recryst.                                             from ethanol-n-hexane)                                                        MS (m/e): 406 (M.sup.+)                                                       IR ν.sub.max.sup.nujol cm.sup.-1 :                                         3360, 3080, 1640                              12 "          H  C(CH.sub.3).sub.3                                                                            m.p. 148-149° C. (recryst.                                             from ethanol-n-hexane)                                                        MS (m/e): 420 (M.sup.+)                                                       IR ν.sub.max.sup.nujol cm.sup.-1 :                                         3380, 3180, 1650                              13 "          H                                                                                 ##STR27##     m.p. 263-264° C. (recryst. from                                        ethyl acetate) MS (m/e): 433 (M.sup.+  +                                      1) IR ν.sub.max.sup.nujol cm.sup.-1 :                                      3260, 3220, 1700, 1625 Sodium salt: m.p.                                      204-209° C. (dec.)                     14 "          H                                                                                 ##STR28##     m.p. 151-153.5° C. (recryst. from                                      ethyl acetate-n-hexane) MS (m/e): 515                                         (M.sup.+  + 3) IR ν.sub.max.sup.nujol                                      cm.sup.-1 : 3215, 3150, 1730, 1720, 1635      15 "          H                                                                                 ##STR29##     m.p. 147-150° C. (recryst. from                                        ethyl acetate-n-hexane) MS (m/e): 521                                         (M.sup.+  + 3) IR ν.sub.max.sup.nujol                                      cm.sup.-1 : 3360, 3160, 1735, 1640            16                                                                                ##STR30## H  (CH.sub.2).sub.2 CO.sub.2 CH.sub.3                                                           m.p. 121-123° C. (recryst. from                                        ethyl acetate-iso- propyl ether) MS                                           (m/e): 462 (M.sup.+  + 1) IR                                                  ν.sub.max.sup.nujol cm.sup.-1 : 3260,                                      3100, 1740, 1640, 1530, 1450, 1160            17                                                                                ##STR31## H  (CH.sub.2).sub.2 CO.sub.2 CH.sub.3                                                           m.p. 115-116° C. (recryst. from                                        methanol-ethyl ether) MS (m/e): 447                                           (M.sup.+  + 1) IR ν.sub.max.sup.nujol                                      cm.sup.-1 : 3390, 3170, 1720, 1650            18                                                                                ##STR32## H  "              m.p. 121-122° C. (recryst. from                                        ethyl acetate-n-hexane) MS (m/e): 467                                         (M.sup.+  + 1) IR ν.sub.max.sup.nujol                                      cm.sup.-1 : 3330, 3270, 1730, 1645            19                                                                                ##STR33## H  "              m.p. 76-78°  C. (recryst. from                                         ethyl acetate) MS (m/e): 423 (M.sup.+  +                                      1) IR ν.sub.max.sup.nujol cm.sup.-1 :                                      3380, 3130, 1740, 1650                        20                                                                                ##STR34## H  (CH.sub.2).sub.3 CO.sub.2 CH.sub.3                                                           m.p. 127-128° C. (recryst. from                                        ethyl acetate-n-hexane) MS (m/e): 445                                         (M.sup.+  + 1) IR ν.sub.max.sup.nujol                                      cm.sup.-1 : 3320, 3260, 1730, 1650            21                                                                                ##STR35## H  (CH.sub.2).sub.3 CO.sub.2 CH.sub.3                                                           m.p. 129-130° C. (recryst. from                                        ethyl acetate-iso- propyl ether) MS                                           (m/e): 499 (M.sup.+  + 1) IR                                                  ν.sub.max.sup.nujol cm.sup.-1 : 3370,                                      3140, 1730, 1643                              22                                                                                ##STR36## H  "              m.p. 118-120° C. (recryst. from                                        ethyl acetate-n-hexane) MS (m/e): 511                                         (M.sup.+  + 3) and 509 (M.sup.+  + 1) IR                                      ν.sub.max.sup.nujol cm.sup.-1 : 3360,                                      3295, 3150 (sh), 3090, 1722, 1650             23                                                                                ##STR37## H  "              m.p. 95-99° C. (recryst. from                                          ethyl acetate-n-hexane) MS (m/e): 431                                         (M.sup.+) IR ν.sub.max.sup.nujol                                           cm.sup.-1 : 3260, 3170, 3090,                 __________________________________________________________________________                                    1720                                      

EXAMPLE 24

(1) A mixture of methyl (2-aminoindan-5-yl)acetate hydrochloride (2.43g), potassium carbonate (5.52 g), water (60 ml), ethyl acetate (60 ml)and 4-chlorophenylsulfonyl chloride (2.11 g) is stirred at roomtemperature for one hour. The ethyl acetate layer is separated from thereaction mixture, washed with aqueous saline solution, dried, anddistilled under reduced pressure to remove the solvent. The resultingcrude product is recrystallized from a mixture of ethyl acetate andn-hexane to give methyl[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (3.02 g).

m.p. 91°-92° C.

MS (m/e): 381 (M⁺ +2), 379 (M⁺)

IR ν_(max) ^(nujol) cm⁻¹ : 3620, 1725

(2) To a solution of the above product (3.0 g) in methanol (40 ml) isadded 1N aqueous sodium hydroxide (20 ml), and the mixture is stirred atroom temperature for one hour and distilled under reduced pressure toremove the solvent. The residue is dissolved in water and adjusted toabout pH 1 with 10% hydrochloric acid and then extracted with ethylacetate. The extract is dried and distilled under reduced pressure toremove the solvent. The resulting crude product is recrystallized from amixture of ethyl acetate and n-hexane to give[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetic acid (2.82 g) ascolorless crystals.

m.p. 159°-161° C.

MS (m/e): 174 (M⁺ - 191)

IR ν_(max) ^(nujol) cm⁻¹ : 3280, 1700

(3) The above product (915 mg), thionyl chloride (2 ml), tetrahydrofuran(20 ml) and methylene chloride (20 ml) are mixed, and the mixture isrefluxed with stirring for 2 hours. After the reaction, the solvent isdistilled off under reduced pressure. The residue is dissolved inmethylene chloride (10 ml), and the solution is added dropwise to amixture of methyl 3-aminopropionate hydrochloride (523 mg),triethylamine (760 mg) and methylene chloride (10 ml) on an ice bath.After stirring the mixture at room temperature for 3 hours, the reactionmixture is distilled under reduced pressure to remove the solvent. Theresidue is extracted with ethyl acetate, and the extract is washed with10% hydrochloric acid, aqueous sodium hydrogen carbonate solution andsaline solution in this order, dried and then distilled under reducedpressure to remove the solvent. The resulting crude crystals arerecrystallized from methylene chloride and n-hexane to give methyl3-[[2-(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionate(962 mg)

m.p. 147°-150° C.

MS (m/e): 450 (M⁺)

IR ν_(max) ^(nujol) cm⁻¹ : 3380, 1715, 1650

EXAMPLES 25 TO 32

(1) In the same manner as described in Example 24-(1), the correspondingstarting compounds are treated to give the compounds of the followingTable 3.

                  TABLE 3                                                         ______________________________________                                         ##STR38##                    (B)                                             Compound B                                                                    R.sup.1        Physical properties, etc.                                      ______________________________________                                         ##STR39##     m.p. 92-93.5° C.*1 MS (m/e): 345 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3300, 1725                   ##STR40##     m.p. 102-104° C.*1 MS (m/e): 359 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3280, 1740                   ##STR41##     m.p. 111-112° C.*1 MS (m/e): 413 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3290, 1740                   ##STR42##     m.p. 105-106° C.*1 MS (m/e): 390 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3280, 1720                   ##STR43##     m.p. 108-110° C.*1 MS (m/e): 375 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3270, 1735                   ##STR44##     m.p. 85-87° C.*1 MS (m/e): 395 (M.sup.+) IR                            ν.sub.max.sup.nujol cm.sup.-1 : 3270, 1730                   ##STR45##     m.p. 87-89° C.*2 MS (m/e): 424 (M.sup.+  + 1) IR                       ν.sub.max.sup.nujol cm.sup.-1 : 3290, 3250, 1720             ##STR46##     m.p. 78-79° C.*1 MS (m/e): 351 (M.sup.+) IR                            ν.sub.max.sup.nujol cm.sup.-1 : 3270,                       ______________________________________                                                       1720                                                            *1 Recrystallized from ethyl acetaten-hexane                                  *2 Recrystallized from isopropanoln-hexane-isopropyl ether               

(2) In the same manner as described in Example 24-(2), the productsobtained in Paragraph (1) are treated to give the compounds of thefollowing Table 4.

                  TABLE 4                                                         ______________________________________                                         ##STR47##                    (C)                                             Compound C                                                                    R.sup.1          Physical properties, etc.                                    ______________________________________                                         ##STR48##       m.p. 123-125° C.*3 MS (m/e): 331 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3550, 3240                 ##STR49##       m.p. 140-141° C.*1 MS (m/e): 345 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3280, 1690                 ##STR50##       m.p. 161-162° C.*1 MS (m/e): 399 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3265, 1695                 ##STR51##       m.p. 173-174° C.*1 MS (m/e): 376 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3285, 1700                 ##STR52##       m.p. 154-155° C.*1 MS (m/e): 361 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3270, 1690                 ##STR53##       m.p. 153-155° C.*1 MS (m/e): 381 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3270, 1705                 ##STR54##       m.p. 167-168.5° C.*1 MS (m/e): 410 (M.sup.+  + 1)                      R ν.sub.max.sup.nujol cm.sup.-1 : 3265, 1698               ##STR55##       m.p. 104-106° C.*1 MS (m/e): 337 (M.sup.+) IR                          ν.sub.max.sup.nujol cm.sup.-1 : 3280,                     ______________________________________                                                         1705                                                          *1 The same as in Table 3                                                     *3 Recrystallized from diethyl ethern-hexane                             

(3) In the same manner as described in Example 24-(3), the productsobtained in Paragraph (2) and methyl 3-aminopropionate (or methyl4-aminobutyrate) are treated to give the same compounds as in Examples16 to 23.

EXAMPLE 33

A mixture of methyl3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionate(720 mg), 1N aqueous sodium hydroxide (3 ml) and methanol (10 ml) isstirred at room temperature for 3 hours and then, the solvent isdistilled off under reduced pressure. The residue is dissolved in water,and the solution is adjusted to pH 1 with 10% hydrochloric acid and isextracted with ethyl acetate. The extract is washed with aqueous salinesolution, dried and then distilled under reduced pressure to remove thesolvent. The resulting crude crystals are recrystallized from ethylacetate - n-hexane to give3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionicacid (656 mg, yield 94%) as colorless crystals.

m.p. 150°-153° C.

MS (m/e): 245 (M⁺ - 191)

IR ν_(max) ^(nujol) cm⁻¹ : 3320, 3270, 1700, 1650

Sodium salt: m.p. 185°-187° C.

EXAMPLES 34 TO 46

In the same manner as described in Example 33, the products obtained inExamples 2, 6, 7 and 14 to 23 are treated to give the compounds of thefollowing Table 5.

                                      TABLE 5                                     __________________________________________________________________________     ##STR56##                                    (D)                             Ex.                                                                              Compound D                                                                 No.                                                                              R.sup.1   R.sup.3                                                                         R.sup.5       Physical properties, etc.                        __________________________________________________________________________    34                                                                                ##STR57##                                                                              H CH.sub.2 CO.sub.2 H                                                                         m.p. 182-185° C. (recryst. from ethyl                                  acetate) MS (m/e): 231 (M.sup.+  - 191) IR                                    ν.sub.max.sup.nujol cm.sup.-1 : 3390,                                      3265, 1720, 1615 Sodium salt: m.p.                                            250-253° C. (dec.)                        35 "         H (CH.sub.2).sub.3 CO.sub.2 H                                                                 m.p. 123.5-125.5° C. (recryst.                                         from THF-isopropyl ether)                                                     MS (m/e): 450 (M.sup.+)                                                       IR ν.sub.max.sup.nujol cm.sup.-1 : 3270,                                   3160, 1700,                                                                   1620, 1150                                                                    Sodium salt:                                                                  m.p. 196.1° C. (dec.)                     36 "         H                                                                                ##STR58##    m.p. 258.5-260.5° C. (recryst. from                                    THF-isopropyl ether) MS (m/e): 485 (M.sup.+                                   + 1) IR ν.sub.max.sup.nujol cm.sup.-1 :                                    3320, 1670 Sodium salt: m.p. 305-311°                                  C. (dec.)                                        37 "         H                                                                                ##STR59##    m.p. 227.5-229.5° C. MS (m/e): 501                                     (M.sup.+  + 3) IR ν.sub.max.sup.nujol                                      cm.sup.-1 : 3300, 2400-2800, 1700, 1682,                                      1640                                             38                                                                                ##STR60##                                                                              H                                                                                ##STR61##    m.p. 190-191.5° C. (dec.) MS (m/e):                                    507 (M.sup.+  + 3) IR ν.sub.max.sup.nujol                                  cm.sup.-1 : 3360, 3140, 3090, 1700, 1640                                      Sodium salt: m.p. >280°  C.               39                                                                                ##STR62##                                                                              H (CH.sub.2).sub.2 CO.sub.2 H                                                                 m.p. 159-161° C. (recryst. from                                        THF-isopropyl ether) MS (m/e): 448 (M.sup.+                                   + 1) IR ν.sub.max.sup.nujol cm.sup.-1 :                                    3350, 3100, 1710, 1650, 1530, 1450, 1340,                                     1160 Sodium salt: m.p. 192-196° C.                                     (dec.)                                           40                                                                                ##STR63##                                                                              H "             foam MS (m/e): 433 (M.sup.+  + 1) IR                                          ν.sub.max.sup.nujol cm.sup.-1 : 3270,                                      1710, 1650                                       41                                                                                ##STR64##                                                                              H "             foam MS (m/e): 453 (M.sup.+  + 1) IR                                          ν.sub.max.sup.nujol cm.sup.-1 : 3260,                                      1710, 1640                                       42                                                                                ##STR65##                                                                              H "             m.p. 87-89° C. (recryst. from ethyl                                    acetate) MS (m/e): 409 (M.sup.+  + 1) IR                                      ν.sub.max.sup.nujol cm.sup.-1 : 3390,                                      3120, 1710, 1650                                 43                                                                                ##STR66##                                                                              H (CH.sub.2).sub.3 CO.sub.2 H                                                                 m.p. 118-119° C. (recryst. from                                        isopropyl alcohol-isopropyl ether) MS (m/e):                                  431 (M.sup.+  + 1) IR ν.sub.max.sup.nujol                                  cm.sup.-1 : 3280, 3180, 1700, 1620 Sodium                                     salt: m.p. 166-168° C.                    44                                                                                ##STR67##                                                                              H (CH.sub.2).sub.3 CO.sub.2 H                                                                 m.p. 150-152° C. (recryst. from                                        ethanol-n-hexane) MS (m/e): 485 (M.sup.+  +                                   1) IR ν.sub.max.sup.nujol cm.sup.-1 :                                      3320, 3280, 1720, 1650 Sodium salt: m.p.                                      197-199° C.                               45                                                                                ##STR68##                                                                              H "             m.p. 122.5-125° C. (recryst. from                                      isopropanol-ethyl ether-water) MS (m/e): 497                                  (M.sup.+  + 3), 495 (M.sup.+  + 1) IR                                         ν.sub.max.sup.nujol cm.sup. -1 : 3270,                                     3170, 3090, 1698 Sodium salt: m.p.                                            197-200° C.                               46                                                                                ##STR69##                                                                              H "             m.p. 128-131° C. (recryst. from                                        isopropanol-ethyl acetate-ethyl ether) MS                                     (m/e): 417 (M.sup.+  + 1) IR                                                  ν.sub.max.sup.nujol cm.sup.-1 : 3270,                                      3170, 3080, 1700 Sodium salt: m.p.                                            153-157° C.                               __________________________________________________________________________

EXAMPLE 47

In the same manner as described in Examples 24 and 33, methyl(2-aminoindan-5-yl)acetate hydrochloride, 4-chlorophenylsulfonylchloride and methyl N-methyl-β-aminopropionate hydrochloride are treatedto give2-[N-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetyl-N-methylamino]aceticacid.

MS (m/e): 436 (M⁺)

IR ν_(max) ^(nujol) (cm⁻¹): 3500, 3200, 1720, 1630

Sodium salt: m.p. 204°-205° C. (dec.)

EXAMPLE 48

A mixture of [2-(4-chlorophenyl)sulfonylamino]indan-5-yl]acetic acid(987 mg), thionyl chloride (2 ml), tetrahydrofuran (10 ml) and methylenechloride (10 ml) is refluxed for 2 hours. After the reaction, thesolvent is distilled off under reduced pressure. The residue isdissolved in tetrahydrofuran (8 ml) (this solution is hereinafterreferred to as "Solution A"). Separately, to a mixture of 5-aminovalericacid (326 mg), diethyl ether (5 ml), 0.6N aqueous sodium hydroxide (5ml) and ethanol (20 ml) are added dropwise Solution A and 0.6N aqueoussodium hydroxide (5 ml) under ice cooling with stirring, and the mixtureis stirred at room temperature overnight. After the reaction, diethylether and water are added to the reaction mixture. The aqueous layer isseparated, acidified with 10% hydrochloric acid and extracted with ethylacetate. The extract is washed with an aqueous saline solution, driedand then distilled under reduced pressure to remove the solvent. Theresidue is purified by silica gel column chromatography (solvent,methanol:chloroform) and further recrystallized from ethyl acetate andisopropyl ether to give5-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-pentanoic acid (661 mg) as colorless solid.

m.p. 156°-157.5° C.

MS (m/e): 464 (M⁺)

IR ν_(max) ^(nujol) cm⁻¹ : 3320, 3260, 1690, 1640

EXAMPLE 49

In the same manner as described in Example 48, the correspondingstarting compound is treated to give6-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-hexanoicacid.

m.p. 163°-164° C.

MS (m/e): 478 (M⁺)

IR ν_(max) ^(nujol) cm⁻¹ : 3280, 3170, 1710, 1620

EXAMPLE 50

(1) Methyl (-)-(2-aminoindan-5-yl)acetate.(-)-dibenzoyl-L-tartaric acidsalt (3.94 g) is added to a mixture of potassium carbonate (4.83 g),water (50 ml) and ethyl acetate (70 ml), and 4-chlorophenylsulfonylchloride (1.49 g) is added thereto. The mixture is stirred at roomtemperature for one hour. The ethyl acetate layer is separated from thereaction mixture, washed with an aqueous sodium hydrogen carbonatesolution, dried, and distilled under reduced pressure to remove thesolvent. The residue is recrystallized from a mixture of ethyl acetateand hexane to give methyl(-)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (2.43 g) ascolorless crystals.

m.p. 80°-82° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3290, 3260, 1725

[α]_(D) ²⁰ -452° (c=1.017, CHCl₃)

(2) To a solution of the above product (1.14 g) in methanol (15 ml) isadded 1N aqueous sodium hydroxide (6 ml), and the mixture is stirred atroom temperature for 2 hours and distilled under reduced pressure toremove the solvent. The residue is acidified with 10% hydrochloric acidand extracted with ethyl acetate. The extract is dried and distilledunder reduced pressure to remove the solvent. The resulting crudeproduct is recrystallized from a mixture of ethyl acetate and hexane togive (-)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetic acid (0.94g).

m.p. 154°-155° C.

IR ν_(max) ^(nujol) (cm⁻¹): 1700

[α]_(D) ²⁰ -8.01° (c=0.512, methanol)

(3) The above product (1.098 g), thionyl chloride (2.4 ml),tetrahydrofuran (15 ml) and methylene chloride (15 ml) are mixed, andthe mixture is refluxed with stirring for 3 hours. After the reaction,the solvent is distilled off under reduced pressure. The residue isdissolved in methylene chloride (15 ml), and the solution is addeddropwise to a mixture of methyl 3-aminopropionate hydrochloride (837mg), triethylamine (1.00 g) and methylene chloride (30 ml) underice-cooling. After stirring the mixture at room temperature for 3 hours,the reaction mixture is distilled under reduced pressure to remove thesolvent. Ethyl acetate and water are added to the residue, and themixture is extracted with ethyl acetate. The extract is washed with 10%hydrochloric acid, saline solution and aqueous sodium bicarbonatesolution in this order, dried and then distilled under reduced pressureto remove the solvent. The residue is recrystallized from a mixture ofmethanol, hexane and isopropyl ether to give methyl(-)-3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionate(1.138 g).

m.p. 110°-113° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3390, 3170, 1725, 1650

[α]_(D) ²⁰ -8.52° (c=0.563, methanol)

(4) A mixture of the above product (992 mg), 1N aqueous sodium hydroxide(4.4 ml) and methanol (8.8 ml) is stirred at room temperature for 2hours. The mixture is acidified with 10% hydrochloric acid and extractedwith ethyl acetate. The extract is washed with water, dried anddistilled under reduced pressure to remove the solvent. The resultingcrude crystals are recrystallized from a mixture of ethyl acetate andhexane to give(-)-3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionicacid (821 mg).

m.p. 141°-142° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3320, 3260, 1695, 1650

[α]_(D) ²⁰⁻ 8.45° (c=0.201, methanol)

EXAMPLES 51 TO 53

(1) In the same manner as described in Examples 50-(1), methyl(+)-(2-aminoindan-5-yl)acetate (+)-dibenzoyl-D-tartaric acid salt and4-chlorophenylsulfonyl chloride are treated to give methyl(+)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate.

m.p. 80°-82° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3290, 3260, 1725

[α]_(D) ²⁰ +4.76° (c=1.049, CHCl₃)

(2) In the same manner as described in Example 50-(2), methyl(+)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate is treated togive (+)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetic acid.

m.p. 154°-155° C.

IR ν_(max) ^(nujol) (cm⁻¹): 1700

[α]_(D) ²⁰ +9.16° (c=0.513, methanol)

(3) In the same manner as described in Example 50-(3), (-)- or(+)-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetic acid and methyl3-aminopropionate or methyl 4-aminobutyrate are treated to give thefollowing compounds.

(i) methyl(+)-3-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-propionate

m.p. 110°-113° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3390, 3170, 1725, 1650

[α]_(D) ²⁰ +8.65° (c=0.566, methanol)

(ii) methyl(-)-4-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-butyrat

m.p. 129.5°-130° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 1730, 1640

[α]_(D) ²⁰ -8.56° (c=0.537, methanol)

(iii) methyl(+)-4-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-butyrate

m.p. 129.5°-130° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 1730, 1640

[α]_(D) ²⁰ +8.47° (c=0.531, methanol)

(4) In the same manner as described in Example 50-(4), the compoundsobtained in Paragraph (3) are treated to give the following compounds.

(i)(+)-3-[[2-[(4-chlorophenyl)sulfonylamino]-indan-5-yl]acetylamino]-n-propionicacid

m.p. 141°-142° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3320, 3260, 1695, 1650

[α]_(D) ²⁰ +8.45° (c=0.201, methanol)

(ii)(-)-4-[[2-[(4-chlorophenyl)sulfonylamino]-indan-5-yl]acetylamino]-n-butyricacid

m.p. 129.5°-131° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3350, 3290, 1720

[α]_(D) ²⁰ -9.3° (c=0.473, tetrahydrofuran)

(iii)(+)-4-[[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetylamino]-n-butyricacid

m.p. 129.5°-131° C.

IR ν_(max) ^(nujol) (cm⁻¹): 3350, 3290, 1720

[α]_(D) ²⁰ +9.33° (c=0.418, tetrahydrofuran)

EXAMPLE 54

[2-[(4-Chlorophenyl)sulfonylamino]indan-5-yl]acetic acid (600 mg) isdissolved in tetrahydrofuran (20 ml) and thereto is added dropwise 7.8Mborane-1,4-oxathiane complex (1 ml). The mixture is stirred at roomtemperature for one hour and thereto is added methanol to terminate thereaction, and then, the solvent is distilled off under reduced pressure.The residue is dissolved in ethyl acetate and washed with aqueous sodiumhydrogen carbonate solution and saline solution, dried and thendistilled under reduced pressure to remove the solvent. The residue ispurified by silica gel column chromatography (solvent, chloroform) togive 2-[2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]ethanol (542 mg) ascolorless crystals.

m.p. 71°-76° C.

MS (m/e): 351 (M⁺)

IR ν_(max) ^(nujol) (cm⁻¹): 3500, 3150 (broad)

REFERENCE EXAMPLE 1

(1) To a solution of 2-aminoindan (19.95 g) in tetrahydrofuran is addedan solution of 2M acetic acid-formic acid anhydride in tetrahydrofuranunder ice cooling, and the mixture is reacted at room temperature. Tothe reaction mixture is added water, and then, the solvent is distilledoff, and the residue is extracted with ethyl acetate. After distillingoff the solvent, the residue is recrystallized from ethyl acetate -n-hexane to give 2-formylaminoindan (19.02 g).

To a solution of the above product (3.22 g) and methylchloro(methylthio)acetate (3.58 g) in methylene chloride is addeddropwise a solution of tin (IV) chloride in methylene chloride undercooling, and the mixture is reacted at room temperature, and thereto isadded water. The mixture is extracted with chloroform. The solvent isdistilled off from the organic layer, and to the residue are addedacetic acid and zinc dust, and the mixture is refluxed. After removingthe zinc dust by filtration, the solvent is distilled off. The residueis extracted with ethyl acetate and the solvent is again distilled offto give ethyl (2-formylaminoindan-5-yl)acetate (4.31 g) as colorlessoil.

IR ν_(max) ^(nujol) (cm⁻¹): 3300, 1730, 1660

(2) To a solution of the above product (2.33 g) in methanol is added 1Naqueous sodium hydroxide, and the mixture is reacted at roomtemperature. The reaction mixture is neutralized with hydrochloric acidand extracted with ethyl acetate. The extract is distilled to remove thesolvent, and the residue is recrystallized from ethyl acetate to give(2-formylaminoindan-5-yl)acetic acid (1.50 g).

m.p. 164°-166° C.

REFERENCE EXAMPLE 2

(2-Benzyloxycarbonylaminoindan-5-yl)acetic acid is obtained in the samemanner as described in Reference Example 1 except that benzyloxycarbonylchloride is used instead of 2M acetic acid-formic acid anhydride.

m.p. 157.5°-158.5° C.

REFERENCE EXAMPLE 3

(1) To a solution of phenylthioacetic acid (8.14 g) in a mixture ofmethylene chloride-tetrahydrofuran is added carbonyldiimidazole underice cooling and the mixture is stirred, and to the reaction mixture areadded β-alanine methyl ester hydrochloride (6.98 g) and triethylamine,and the mixture is reacted. After the reaction, the solvent is distilledoff under reduced pressure. The residue is extracted with ethyl acetate.The extract is distilled to remove the solvent, and the residue isrecrystallized from ethyl acetate - n-hexane to give methyl3-[(phenylthio)-acetylamino]-n-propionate (10.95 g).

m.p. 62°-63° C.

(2) To a solution of the above product (6.35 g) in methylene chloride isadded N-chlorosuccinimide (3.50 g), and the mixture is reacted. Afterthe reaction, the solvent is distilled off, and to the residue is addedcarbon tetrachloride, and the mixture is filtered. The filtrate isconcentrated, and the residue is recrystallized from n-hexane to givemethyl 3-[chloro(phenylthio)acetylamino]-n-propionate (7.12 g).

m.p. 49°-52° C.

REFERENCE EXAMPLE 4

Methyl 4-[chloro(phenylthio)acetylamino]-n-butyrate is obtained in thesame manner as described in Reference Example 3 except that methyl4-aminobutyrate is used instead of β-alanine methyl ester.

m.p. 38°-40° C.

REFERENCE EXAMPLE 5

(1) To a mixture of 2-aminoindan hydrochloride (10.40 g), potassiumcarbonate (34.2 g), water (100 ml) and ethyl acetate (150 ml) is addeddropwise acetyl chloride (9.68 g) under ice cooling. The mixture isstirred at 0° C. for 1.5 hour, and the ethyl acetate layer is separated,washed with aqueous saline solution, dried, and then the solvent isdistilled off under reduced pressure. The residue is recrystallized fromethyl acetate - n-hexane to give 2-acetylaminoindan (9.5 g) as colorlesscrystals. m.p. 126.5°-127.5° C.

(2) To a mixture of the above product (13.06 g), ethylchloro(methylthio)acetate (13.35 g) and methylene chloride (100 ml) isadded dropwise a solution of stannic chloride (40.0 g) in methylenechloride (50 ml) under ice cooling. The mixture is stirred at 0° C. toroom temperature for 2 hours, and the reaction mixture is poured ontoice and then extracted with ethyl acetate. The extract is washed with10% hydrochloric acid, aqueous sodium hydrogen carbonate solution andaqueous saline solution in this order, dried, and then distilled underreduced pressure to remove the solvent. The residue (24.3 g) isdissolved in acetic acid (150 ml) and thereto is added zinc dust (100g), and the mixture is refluxed for 2 hours. After cooling, the mixtureis filtered, and the filtrate is concentrated under reduced pressure,and then, acetic acid is distilled off. To the residue are added waterand ethyl acetate, and the ethyl acetate layer is separated, washed withaqueous sodium hydrogen carbonate solution and aqueous saline solution,dried and distilled under reduced pressure to remove the solvent. Thecrude crystals thus obtained are recrystallized from diethyl ether -n-hexane to give ethyl (2-acetylaminoindan-5-yl)acetate (15.67 g) ascolorless crystals. m.p. 82°-84° C.

(3) A mixture of the above product (16.69 g) and 2N hydrochloric acid(100 ml) is refluxed for 18 hours. After the reaction, the solvent isdistilled off under reduced pressure. Methanol (100 ml) is added to theresidue and the mixture is refluxed for one hour. After cooling, thesolvent distilled off under reduced pressure. The crude crystals thusobtained are recrystallized from a mixture of methanol, isopropanol andisopropyl ether to give methyl (2-aminoindan-5-yl)acetate (15.14 g) ascolorless crystals.

m.p. 145°-148° C.

(4) Methyl (2-aminoindan-5-yl)acetate (10.89 g) is added to 1N aqueoussodium bicarbonate solution (200 ml), and the mixture is extracted withchloroform. The extract is dried and distilled under reduced pressure toremove the solvent. The residue is dissolved in 90% aqueous methanol(300 ml) and thereto is added a solution of (-)-dibenzoyl-L-tartaricacid hydrate (16.93 g) in 90% aqueous methanol (200 ml). The mixture isallowed to stand for 2 days, and the resulting crude crystals arerecrystallized from 90% aqueous methanol to give methyl(-)-(2-aminoindan-5-yl)acetate.(-)-dibenzoyl-L-tartaric acid salt (4.71g).

m.p. 184°-184.5° C.

[α]_(D) ²⁰ -79.2° (c=0.202, 50% methanol)

The mothor liquor obtained above is distilled under reduced pressure toremove the solvent, and to the residue are added water (200 ml) andpotassium carbonate (11.75 g). The mixture is extracted with chloroform,and the extract is dried and distilled under reduced pressure to removethe solvent. The residue is dissolved in 90% aqueous methanol andthereto is added a solution of (+)-dibenzoyl-D-tartaric acid hydrate(10.60 g) in 90% aqueous methanol. The mixture is allowed to stand, andthe resulting crude crystals are recrystallized from 90% aqueousmethanol to give methyl(+)-(2-aminoindan-5-yl)-acetate.(+)-dibenzoyl-D-tartaric acid salt (5.12g).

m.p. 184°-184.5° C.

[α]_(D) ²⁰ +79.51° (c=0.205, 50% methanol)

EXPERIMENTS

(1) Effect on bronchoconstriction (in vivo)

Hartley-male guinea pigs were anesthetized with α-chloralose (120 mg/kg,i.v.), and a tracheal cannula was inserted to each of the guinea pigs.Each one of the guinea pigs was immobilized by administration ofgallamine triethiotide (5 mg/kg, i.v.) under artificial respiration (ca.1.0 ml/100 g, 60 strokes/min). The volume of the artificial respirationwas regulated so that the peak of intratracheal pressure (ITP) was ca.10 cm H₂ O. The change of ITP was measured by a pressure-transducerconnected to the tracheal cannula. After 0.3, 0.7 and 2 μg/kg of U-46619(11,9-epoxymethano-PGH₂) were administered to each of the guinea pigsintravenously (or intraduodenally) at 30-minute intervals and thereaction of administration of U-46619 was stabilized, the solution of atest compound in physiological saline was administered to lateralsaphenous vein of the guinea pig five minutes before administration ofU-46619, and the change of the ITP was measured. The Inhibition wascalculated according to the following formula. ##EQU1##

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Administration                                                                            administration                                                                              Inhibition                                                                             ED.sub.50                                  route       dose (mg/kg)  (%)      (mg/kg)                                    ______________________________________                                        intravenously                                                                             0.3           12       0.62                                                   1             78                                                              3             100                                                 intraduodenally                                                                           3             49       3                                                      10            70                                                  ______________________________________                                    

(2) Effect on bronchoconstriction (in vivo)

Hartley-male guinea pigs were anesthetized with α-chloralose (120 mg/kg,i.v.), and a tracheal cannula was inserted to each of the guinea pigs.Each one of the guinea pigs was immobilized by administration ofgallamine triethiotide (5 mg/kg, i.v.) under artificial respiration (ca.1.0 ml/100 g, 60 strokes/min). The volume of the artificial respirationwas regulated so that the peak of intratracheal pressure (ITP) was ca.10 cm H₂ O. The change of ITP was measured 150 minutes afteradministration of the test compounds by a pressure-transducer connectedto the tracheal cannula. After 30 μg/kg of PGD₂ were administered toeach of the guinea pigs intravenously at 30-minute intervals and thereaction of administration of PGD₂ was stabilized, the solution of atest compound in physiological saline was administered to lateralsaphenous vein of the guinea pig, and the change of the ITP wasmeasured. The Inhibition was calculated according to the followingformula. ##EQU2##

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Administration                                                                            administration                                                                              Inhibition                                                                             ED.sub.50                                  route       dose (mg/kg)  (%)      (mg/kg)                                    ______________________________________                                        intravenously                                                                             0.1           40       0.17                                                   0.3           70                                                              1             80                                                              3             85                                                  ______________________________________                                    

(3) Effect on antigen-induced bronchoconstriction

Hartley-male guinea pigs were passively sensitized by intravenousinjection of rabbit antiserum against ovalbumin (0.1 ml/100 g of bodyweight). 24 hours later, the animals were anesthetized with α-chloralose(120 mg/kg, i.v.), and after a tracheal cannula was inserted to them,the animals were immobilized by administration of gallamine triethiotide(5 mg/kg, i.v.) under artificial respiration (ca. 1.0 ml/100 g, 60strokes/min). Lung volume changes were measured as overflow of air fromthe lung by the modified Konzett-Rossler method (cf. Arch. Exp. pathol.Pharmakol., 195, 71 (1940)). The test compound was administeredintravenously (or orally) to the animals five minutes before saidanimals were challenged with an antigen (ovalbumin, 30 μg/kg, i.v.).Mepyramine was administered to the animals 10 minutes before saidanimals was administered the antigen.

The bronchoconstriction was estimated by comparing the increase inventilation overflow volume by an artificial blockade of a trachea andthat by an administration of an antigen. The inhibitory effect of a testcompound was calculated according to the following formula. ##EQU3##

The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Administration administration                                                                           Inhibition                                          route          dose (mg/kg)                                                                             (%)                                                 ______________________________________                                        intravenously   10        70                                                  orally         100        67                                                  ______________________________________                                    

(4) Effect on bronchoconstriction (in vivo)

Male and female dogs were anesthetized with sodium pentobarbital (PB: 30mg/kg, i.v.), and a tracheal cannula was inserted to each of the dogs.After thoracotomy, the following experiment was carried out underartificial respiration (ca. 1.0 ml/100 g, 60 strokes/min). The volume ofthe artificial respiration was regulated so that the peak ofintratracheal pressure (ITP) was ca. 10 cm H₂ O. The change of ITP wasmeasured by a pressure-transducer connected to the tracheal cannula.After 0.3, 0.7 and 2 μg/kg of U-46619 were administered to each of theguinea pigs intravenously (or intraduodenally) at 30-minute intervalsand the reaction of administration of U-46619 was stabilized, thesolution of a test compound in physiological saline was administered tolateral saphenous vein of the guinea pig five minutes beforeadministration of U-46619, and the change of the ITP was measured. TheInhibition was calculated according to the following formula. ##EQU4##

The results are shown in Table 4.

                  TABLE 4                                                         ______________________________________                                        Administration                                                                            administration                                                                              Inhibition                                                                             ED.sub.50                                  route       dose (mg/Kg)  (%)      (mg/kg)                                    ______________________________________                                        intravenously                                                                             0.03          20       0.11                                                   0.1           50                                                              0.2           80                                                              1             95                                                              3             100                                                             10            100                                                 intraduodenally                                                                           0.3           80       --                                         ______________________________________                                    

What is claimed is:
 1. A method for the treatment or prophylaxis ofthromboses in a warm-blooded animal which comprises administering aneffective amount of a compound having the formula: ##STR70## wherein R¹is a phenyl group or a phenyl group substituted by a member selectedfrom the group consisting of a C₁ -C₅ alkyl group, a C₁ -C₅ alkoxygroup, a halogen atom, trifluoromethyl, and nitro, or a naphthyl group,and R² is a hydroxymethyl group or a group of the formula: ##STR71##wherein R³ is hydrogen atom or a C₁ -C₅ alkyl group and R⁴ is a C₃ -C₆cycloalkyl group, a C₂ -C₆ alkoxycarbonyl-phenyl group, carboxy-phenylgroup, a C₁ -C₅ alkyl group, or a C₁ -C₅ alkyl group having asubstituent selected from a C₁ -C₅ alkoxycarbonyl group, carboxy group,a C₂ -C₆ alkoxycarbonylphenyl group, a carboxy-phenyl group, a C₂ -C₆alkoxycarbonyl-(C₃ -C₆)cycloalkyl group and a carboxy-(C₃ -C₆)cycloalkylgroup, or a pharmaceutically acceptable salt thereof to said warmblooded animal.
 2. The method according to claim 1, wherein in saidcompound, R¹ is chlorophenyl, and R⁴ is carboxyphenyl or a C₁ -C₄ alkylsubstituted by a carboxy, or a pharmaceutically acceptable salt thereof.3. A method for the treatment or prophylaxis of asthma in a warm-bloodedanimal which comprises administering an effective amount of a compoundhaving the formula: ##STR72## wherein R¹ is a phenyl group or a phenylgroup substituted by a member selected from the group consisting of a C₁-C₅ alkyl group, a C₁ -C₅ alkoxy group, a halogen atom, trifluoromethyl,and nitro, or a naphthyl group, and R² is a hydroxymethyl group or agroup of the formula: ##STR73## wherein R³ is a hydrogen atom or a C₁-C₅ alkyl group and R⁴ is a C₃ -C₆ cycloalkyl group, a C₂ -C₆alkoxycarbonyl-phenyl group, carboxy-phenyl group, a C₁ -C₅ alkyl group,or a C₁ -C₅ alkyl group having a substituent selected from a C₁ -C₅alkoxycarbonyl group, carboxy group, a C₂ -C₆ alkoxycarbonylphenylgroup, a carboxy-phenyl group, a C₂ -C₆ alkoxycarbonyl-(C₃-C₆)cycloalkyl group and a carboxy-(C₃ -C₆)cycloalkyl group, or apharmaceutically acceptable salt thereof to said warm blooded animal. 4.The method according to claim 3, wherein in said compound, R¹ ischlorophenyl, and R⁴ is carboxyphenyl or a C₁ -C₄ alkyl substituted by acarboxy, or a pharmaceutically acceptable salt thereof.